The invention allows the preparation of oxazoles in high yield and great purity. Oxazoles constitute valuable intermediates in the synthesis of pharmaceutically active substances, for example PPAR agonists. Appropriate examples of PPAR agonists are described, inter alia, in WO 03/020269, WO 2004/075815, WO 2004/076447, WO 2004/076428, WO 2004/076426, WO 2004/076427, DE 102004039533.0, DE 102004039532.2, DE 102004039509.8. The latter are medicaments which can have a positive influence both on lipid metabolism and on glucose metabolism.
The condensation of aromatic aldehydes with α-ketoximes to give N-oxides and the subsequent reaction with activated acid derivatives to give oxazoles is known per se. For the conversion of the N-oxides to the oxazoles, the literature describes the reagents phosphorus (III) chloride (PCl3) and phosphorus oxychloride (POCl3) and, in one variant, acetic anhydride ((CH3COO)2O) (Y. Goto, M. Yamazaki, M. Hamana, Chem Pharm Bull. 19 (1971) 2050, and literature cited there). These reagents are not widely applicable and often lead to no products or to highly contaminated products which can only be obtained in sufficient purity with low yields in a costly and inconvenient manner, for example by chromatographic processes.
The reaction conditions described require the isolation of the N-oxides. For N-oxides with exothermic decomposition potential, this constitutes a considerable safety risk and prevents the process from being practiced on the industrial scale.
It has now been found that, surprisingly, the transformation of the N-oxides to the halomethyloxazoles proceeds unexpectedly smoothly with high yield and great purity with inorganic thionyl halides or organic sulfonyl halides.
Although it was unexpected on the basis of the remarks in the literature, halomethyloxazoles in some cases precipitate cleanly directly out of the reaction mixture in the form of the free base or as salts.
Unexpectedly, for N-oxides with exothermic decomposition potential, it has been possible to achieve both safe preparation in dilute solution and the further direct reaction of the solution to give the halomethyloxazoles.